Carboxylic acid derivatives, their preparation and use

ABSTRACT

Carboxylic acid derivatives 
                         
where R-R 6 , X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.

Two (2) reissue applications have been co-filed for the reissue of U.S.Pat. No. 5,932,730. The reissue applications are U.S. Ser. No.12/481,594 (the present application) and U.S. Ser. No. 12/481,598 (aco-filed reissue application), all of which are co-filed reissues ofU.S. Pat. No. 5,932,730.

The present invention relates to novel carboxylic acid derivatives,their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and issynthesized and released by the vascular endothelium. Endothelin existsin three isoforms, ET-1, ET-2 and ET-3. In the following text,“endothelin” or “ET” signifies one or all isoforms of endothelin.Endothelin is a potent vasoconstrictor and has a potent effect on vesseltone. It is known that this vasoconstriction is caused by binding ofendothelin to its receptor (Nature, 332, (1988) 411-415; FEBS Letters,231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988)868-875).

Increased or abnormal release of endothelin causes persistentvasoconstruction in the peripheral, renal and cerebral blood vessels,which may lead to illnesses. It has been reported in the literature thatelevated plasma levels of endothelin were found in patients withhypertension, acute myocardial infarct, pulmonary hypertension,Raynaud's syndrome, atherosclerosis and in the airways of asthmatics(Japan J. Hypertension, 12, (1989) 79, J. Vascular Med. Biology 2,(1990) 207, J. Am. Med. Association 264, (1990) 2868).

Accordingly, substances which specifically inhibit the binding ofendothelin to the receptor ought also to antagonize the variousabovementioned physiological effects of endothelin and therefore bevaluable drugs.

We have found that certain carboxylic acid derivatives are goodinhibitors of endothelin receptors.

The invention relates to carboxylic acid derivatives of the formula I

where R is formyl, tetrazole [sic], nitrile [sic], a COOH group —COOH ora radical which can be hydrolyzed to —COOH, and the other substituentshave the following meanings:

-   -   R² is hydrogen, hydroxyl, —NH₂, —NH(C₁-C₄-alkyl),        —N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;    -   X is nitrogen or CR¹⁴ where R¹⁴ is hydrogen or C₁₋₅ C₁-C₅-alkyl,        or CR¹⁴ forms together with CR³ a 5- or 6-membered alkylene or        alkenylene ring which can be substituted by one or two C₁₋₄        C₁-C₄-alkyl groups and in which in each case a methylene group        can be replaced by oxygen, sulfur, —NH— or —NC₁₋₄(C₁-C₄-alkyl)—;    -   R³ is hydrogen, hydroxyl, —NH₂, —NH(C₁-C₄-Alkyl alkyl),        —N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, —NH—O—C₁₋₄C₁-C₄-alkyl,        C₁-C₄-alkylthio or CR³ is linked to CR¹⁴ as indicated above to        give a 5- or 6-membered ring;    -   R⁴ and R⁵ (which can be identical or different) are:        -   phenyl or naphthyl, which can be substituted by one or more            of the following radicals: halogen, nitro, cyano, hydroxyl,            C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,            C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, amino,            C₁-C₄-alkylamino or C₁-C₄-dialkylamino; or        -   phenyl or naphthyl, which are connected together in the            ortho positions via a direct linkage, a methylene, ethylene            or ethenylene group, an oxygen or sulfur atom or an —SO₂—,            —NH— or N-alkyl group, or C₃-C₇-cycloalkyl;    -   R⁶ is hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or        C₃-C₈-cycloalkyl, where each of these radicals can be        substituted one or more times by: halogen, nitro, cyano,        C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy,        C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl,        C₁-C₄-alkoxycarbonyl, C₃₋₈ C₃-C₈-alkylcarbonylalkyl,        C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, phenyl or phenyl or        phenoxy which is substituted one or more times, eg. e.g., one to        three times, by halogen, mitro nitro, cyano, C₁-C₄-alkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or        C₁-C₄-alkylthio;        -   phenyl or naphthyl, each of which can be substituted by one            or more of the following radicals: halogen, nitro, cyano,            hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,            C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio,            C₁-C₄-alkylamino, C₁-C₄-dialkylamino, dioxomethylene [sic]            or dioxoethylene [sic]; or        -   a five- or six-membered heteroaromatic moiety containing one            to three nitrogen atoms and/or one sulfur or oxygen atom,            which can carry one to four halogen atoms and/or one or two            of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl,            phenoxy or phenylcarbonyl, it being possible for the phenyl            radicals in turn to carry one to five halogen atoms and/or            one to three of the following radicals: C₁-C₄-alkyl,            C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or            C₁-C₄-alkylthio;        -   with the proviso that R⁶ can be hydrogen only when Z is not            a single bond;    -   Y is sulfur or, oxygen or a single bond;    -   Z is sulfur or, oxygen or a single bond.

The compounds, and the intermediates for preparing them, such as IV andVI, may have one or more asymmetrical substituted carbon atoms. Suchcompounds may be in the form of the pure enantiomers or purediastereomers or a mixture thereof. The use of an enantiomerically purecompound as active substance is preferred.

The invention furthermore relates to the use of the above-mentionedcarboxylic acid derivatives for producing drugs, in particular forproducing endothelin receptor inhibitors.

The invention furthermore relates to the preparation of the compounds ofthe formula IV in enantiomerically pure form. Enantioselectiveepoxidation of an olefin with two phenyl substituents is known (J. Org.Chem. 59, 1994, 4378-4380). We have now found, surprisingly, that evenester groups in these systems permit epoxidation in high optical purity.

The preparation of the compounds according to the invention where Z issulfur or oxygen starts from the epoxides IV, which are obtained in aconventional manner, eg. e.g., as described in J. March, AdvancedOrganic Chemistry, 2nd ed., 1983, page 862 and page 750, from theketones II or the olefins III:

Carboxylic acid derivatives of the general formula VI can be prepared byreacting the epoxides of the general formula IV (eg. e.g., with R═ROOR¹⁰[sic]) with alcohols or thiols of the general formula V where R⁶ and Zhave the meanings stated in claim 1.

To do this, compounds of the general formula IV are heated withcompounds of the formula V, in the molar ratio of about 1:1 to 1:7,preferably 1 to 3 mole equivalents, to 50-200° C., preferably 80-150° C.

The reaction can also take place in the presence of a diluent. Allsolvents which are inert toward the reagents used can be used for thispurpose.

Examples of such solvents or diluents are water, aliphatic, alicyclicand aromatic hydrocarbons, which may in each case be chlorinated, suchas hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene,xylene, methylene chloride, chloroform, carbon tetrachloride, ethylchloride and trichloroethylene, ethers such as diisopropyl ether,dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane andtetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methylisopropyl ketone and methyl isobutyl ketone, nitriles such asacetonitrile and propionitrile, alcohols, such as methanol, ethanol,isopropanol, butanol and ethylene glycol, esters such as ethyl acetateand amyl acetate, amides such as dimethylformamide, dimethylacetamideand N-methylpyrrolidone, sulfoxides and sulfones, such as dimethylsulfoxide and sulfolane, bases such as pyridine, cyclic ureas such as1,3-dimethylimidazolidin-2-one and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

The reaction is preferably carried out at a temperature in the rangefrom 0° C. to the boiling point of the solvent or mixture of solvents.

The presence of a catalyst may be advantageous. Suitable catalysts arestrong organic and inorganic acids, and Lewis acids. Examples thereofare, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid,p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV)alcoholates.

Compounds of the formula VI where R⁴ and R⁵ are cycloalkyl can also beprepared by subjecting compounds of the formula VI where R⁴ and R⁵ arephenyl, naphthyl, or phenyl or naphthyl substituted as described above,to a nuclear hydrogenation.

Compounds of the formula VI can be obtained in enantiomerically pureform by starting from enantiomerically pure compounds of the formula IVand reacting them in the manner described with compounds of the formulaV.

It is furthermore possible to obtain enantiomerically pure compounds ofthe formula VI by carrying out a classical racemate resolution onracemic or diastereomeric compounds of the formula VI using suitableenantiomerically pure bases such as brucine, strychnine, quinine,quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine,dehydroabietylamine, ephedrine (−), (+), deoxyephedrine (+), (−),threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (−),threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (−)threo-2-amino-1-phenyl-1,3-propanediol (+), (−), α-methylbenzylamine(+), (−), α-(1-naphthyl)ethylamine (+), (−), α-(2-naphthyl)ethylamine(+), (−), aminomethylpinane, N,N-dimethyl-1-phenylethylamine,N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine,norephedrine, norpseudoephedrine, amino acid derivatives, peptidederivatives.

The compounds according to the invention where Y is oxygen, and theremaining substituents have the meanings stated under the generalformula I, can be prepared, for example, by reacting the carboxylic acidderivatives of the general formula VI where the substituents have thestated meanings with compounds of the general formula VII

where R¹⁵ is halogen or R¹⁶—SO₂—, where R¹⁶ can be C₁-C₄-alkyl,C₁-C₄-haloalkyl or phenyl. The reaction preferably takes place in one ofthe abovementioned inert diluents with the addition of a suitable base,ie. i.e., of a base which deprotonates the intermediate VI, in atemperature range from room temperature to the boiling point of thesolvent.

Compounds of the formula VII are known, some of them can be bought, orthey can be prepared in a generally known manner.

It is possible to use as a base an alkali metal or alkaline earth metalhydride such as sodium hydride, potassium hydride or calcium hydride, acarbonate such as an alkali metal carbonate, eg. e.g., sodium orpotassium carbonate, an alkali metal or alkaline earth metal hydroxidesuch as sodium or potassium hydroxide, an organometallic compound suchas butyllithium, or an alkali metal amide such as lithiumdiisopropylamide.

The compounds according to the invention where Y is sulfur, and theremaining substituents have the meanings stated under the generalformula I, can be prepared, for example, by reacting carboxylic acidderivatives of the general formula VIII, which can be obtained in aknown manner from compounds of the general formula VI and in which thesubstituents have the abovementioned meanings, with compounds of thegeneral formula IX, where R², R³ and X have the meanings stated undergeneral formula I.

The reaction preferably takes place in one of the above-mentioned inertdiluents with the addition of a suitable base, ie. i.e., a base whichdeprotonates the intermediate IX, in a temperature range from roomtemperature to the boiling point of the solvent.

It is possible to use as a base, besides those mentioned above, organicbases such as triethylamine, pyridine, imidazole or diazabicycloundecane[sic].

Carboxylic acid derivatives of the formula VIa (z in formula VI=directlinkage) can be prepared by reacting epoxides of the formula IV withcuprates of the formula XI:

The cuprates can be prepared as described in Tetrahedron Letters 23,(1982) 3755.

Compounds of the formula I can also be prepared by starting from thecorresponding carboxylic acids, ie. i.e., compounds of the formula Iwhere R is COOH, and initially converting these in a conventional mannerinto an activated form, such as a halide, an anhydride or imidazolide,and then reacting the latter with an appropriate hydroxy compound HOR¹⁰.This reaction can be carried out in the usual solvents and oftenrequires addition of a base, in which case those mentioned above aresuitable. These two steps can also be simplified, for example, byallowing the carboxylic acid to act on the hydroxy compound in thepresence of a dehydrating agent such as a carbodiimide.

In addition, it is also possible for compounds of the formula I to beprepared by starting from the salts of the corresponding carboxylicacids, ie. i.e., from compounds of the formula I where R is COR¹ and R¹is OM, where M can be an alkali metal cation or the equivalent of analkaline earth metal cation. These salts can be reacted with manycompounds of the formula R¹-A where A is a conventional nucleofugicleaving group, for example halogen such as chlorine, bromine, iodine oraryl- or alkylsulfonyl which is unsubstituted or substituted by halogen,alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, oranother equivalent leaving group. Compounds of the formula R¹-A with areactive substituent A are known or can be easily obtained with generalexpert knowledge. This reaction can be carried out in conventionalsolvents and advantageously takes place with the addition of a base, inwhich case those mentioned above are suitable.

The radical R in formula I may vary widely. For example, R is a group

where R¹ has the following meanings:

-   -   a) hydrogen;    -   b) succinylimidoxy [sic];    -   c) a five-membered heteroaromatic moiety linked by a nitrogen        atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl,        which may carry one or two halogen atoms, in particular fluorine        and chlorine and/or one or two of the following radicals:        -   C₁-C₄-alkyl such as methyl, ethyl, 1-propyl, 2-propyl,            2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;        -   C₁-C₄-haloalkyl, in particular C₁-C₂-haloalkyl such as            fluoromethyl, difluoromethyl, trifluoromethyl,            chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl,            1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,            2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,            2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and            pentafluoroethyl;        -   C₁-C₄-haloalkoxy, in particular C₁-C₂-haloalkoxy such as            difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy,            1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,            1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy,            2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, in            particular trifluoromethoxy;        -   C₁-C₄-alkoxy such as methoxy, ethoxy, propoxy,            1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy,            1,1-dimethylethoxy, in particular methoxy, ethoxy,            1-methylethoxy;        -   C₁-C₄-alkylthio such as methylthio, ethylthio, propylthio,            1-methylethylthio, butylthio, 1-methylpropylthio,            2-methylpropylthio, 1,1-dimethylethylthio, in particular            methylthio and ethylthio;    -   d) R¹ is furthermore a radical

-   -    where m is 0 or 1 and R⁷ and R⁸, which can be identical or        different, have the following meanings:        -   hydrogen;        -   C₁-C₈-alkyl, in particular C₁-C₄-alkyl as mentioned above;        -   C₃-C₆-alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl,            1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl,            3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl,            2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,            2-methyl-3-butenyl, 3-methyl-3-butenyl,            1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl,            1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,            5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,            3-methyl-2-pentenyl, 4-methyl-2-pentenyl,            3-methyl-3-pentenyl, 4-methyl-3-pentenyl,            1-methyl-4-pentenyl, 2-methyl-4-pentenyl,            3-methyl-4-pentenyl, 4-methyl-4-pentenyl,            1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,            1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,            1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,            2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl,            2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl,            1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,            1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and            1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl,            2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl;        -   C₃-C₆-alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl,            1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,            1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl,            1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl,            3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,            1-methyl-2-pentynyl, 1-methyl-3-pentynyl,            1-methyl-4-pentynyl, 2-methyl-3-pentynyl,            2-methyl-4-pentynyl, 3-methyl-4-pentynyl,            4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,            1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,            2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl,            1-ethyl-3-butynyl, 2-ethyl-3-butynyl and            1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl,            2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, in            particular 2-propynyl; or        -   C₃-C₈-cycloalkyl such as cyclopropyl, cyclobutyl,            cyclopentyl, cyclohexyl and, cycloheptyl, and cyclooctyl,            where these alkyl, cycloalkyl, alkenyl and alkynyl groups            can each carry one to five halogen atoms, in particular            fluorine or chlorine and/or one or two of the following            groups:            -   C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio,                C₁-C₄-haloalkoxy as mentioned above, C₃-C₆-alkenyloxy,                C₃-C₆-alkenylthio, C₃-C₆-alkynyloxy, C₃-C₆-alkynylthio,                where the alkenyl and alkynyl constituents present in                these radicals preferably have the abovementioned                meanings;            -   C₁-C₄-alkylcarbonyl such as, in particular,                methylcarbonyl, ethylcarbonyl, propylcarbonyl,                1-methylethylcarbonyl, butylcarbonyl, 1-                methylpropylcarbonyl, 2-methylpropylcarbonyl,                1,1-dimethylethylcarbonyl;            -   C₁-C₄-alkoxycarbonyl such as methoxycarbonyl,                ethoxycarbonyl, propyloxycarbonyl,                1-methylethoxycarbonyl, butyloxycarbonyl,                1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl,                1,1-dimethylethoxycarbonyl;            -   C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl,                C₃-C₆-alkenyloxycarbonyl and C₃-C₆-alkynyloxycarbonyl,                where the alkenyl and alkynyl radicals are preferably                defined as detailed above;            -   phenyl, unsubstituted or substituted one or more times,                eg. e.g., one to three times, by halogen, nitro, cyano,                C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,                C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, such as                2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl,                2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl,                2-trifluoromethylphenyl, 3-methoxyphenyl,                4-trifluoroethoxyphenyl, 2-methylthiophenyl,                2,4-dichlorophenyl, 2-methoxy-3-methylphenyl,                2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl,                2,6-difluorophenyl;            -   di-C₁-C₄-alkylamino such as, in particular,                dimethylamino, dipropylamino, N-propyl-N-methylamino,                N-propyl-N-ethylamino, diisopropylamino,                N-isopropyl-N-methylamino, N-isopropyl-N-ethylamino,                N-isopropyl-N-propylamino;            -   R⁷ and R8 R⁸ are furthermore phenyl which can be                substituted by one or more, eg. e.g., one to three, of                the following radicals: halogen, nitro, cyano,                C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,                C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, as mentioned above                in particular;            -   or R⁷ and R⁸ together form a C₄-C₇-alkylene chain which                is closed to form a ring, is unsubstituted or                substituted, eg. e.g., substituted by C₁-C₄-alkyl, and                may contain a heteroatom selected from the group                consisting of oxygen, sulfur or nitrogen, such as                —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—,                —(CH₂)₂—O—(CH₂)₂—, —CH₂—S—(CH₂)₃—, —(CH₂)₂—O—(CH₂)₃—,                —NH—(CH₂)₃—, —CH₂—NH—(CH₂)₂—, —CH₂—CH═CH—CH₂—,                —CH═CH—(CH₂)—₃—;    -   e) R¹ is furthermore a group

-   -   -   where k is 0, 1 and 2,;        -   p is 1, 2, 3 and 4; and        -   R⁹ is C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-alkenyl,            C₃-C₆-alkynyl or unsubstituted or substituted phenyl, as            mentioned above in particular.;

    -   f) R¹ is furthermore a radical OR¹⁰, where R¹⁰ is:        -   hydrogen, the cation of an alkali metal such as lithium,            sodium, potassium or the cation of an alkaline earth metal            such as calcium, magnesium and barium or an environmentally            compatible organic ammonium ion such as tertiary            C₁-C₄-alkylammonium or the ammonium ion;        -   C₃-C₈-cycloalkyl as mentioned above, which may carry one to            three C₁-C₄-alkyl groups;        -   C₁-C₈-alkyl such as, in particular, methyl, ethyl, propyl,            1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,            1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,            3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,            2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl,            2-methylpentyl, 3-methylpentyl, 4-methylpentyl,            1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbuty            1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,            1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,            2-ethylbutyl, 1-ethyl-2-methylpropyl, which can carry one to            five halogen atoms, in particular fluorine and chlorine            and/or one of the following radicals:            -   C₁-C₄alkoxy, C₁-C₄-alkylthio, cyano,                C₁-C₄-alkylcarbonyl, C₃-C₈-cycloalkyl,                C₁-C₄-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl,                where the aromatic radicals in turn can carry in each                case one to five halogen atoms and/or one to three of                the following radicals: nitro, cyano, C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or                C₁-C₄-alkylthio, as mentioned above in particular;            -   a C₁-C₈-alkyl as mentioned above, which can carry one to                five halogen atoms, in particular fluorine and/or                chlorine, and carries one of the following radicals: a                5-membered heteroaromatic moiety containing one to three                nitrogen atoms, or a 5-membered heteroaromatic moiety                containing a nitrogen atom and an oxygen or sulfur atom,                which can carry one to four halogen atoms and/or one or                two of the following radicals:                -   nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,                    C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or                    C₁-C₄-alkylthio. Particular mention may be made of:                    1-pyrazolyl, 3-methyl-1-pyrazolyl,                    4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl,                    3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl,                    4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl,                    1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl,                    3-methyl-1,2,4-triazol-1-yl,                    5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl,                    3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl,                    2-oxazolyl, 2-thiazolyl, 2-imidazolyl,                    3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl,                    3-tert-butyl-5-isoxazolyl;            -   a C₂-C₆-alkyl group which carries one of the following                radicals in position 2: C₁-C₄-alkoxyimino,                C₃-C₆-alkynyloxyimino, C₃-C₆-haloalkenyloxyimino or                benzyloxyimino; or            -   a C₃-C₆-alkenyl or C₃-C₆-alkynyl group, it being                possible for these groups in turn to carry one to five                halogen atoms;            -   R¹⁰ is furthermore a phenyl radical which can carry one                to five halogen atoms and/or one to three of the                following radicals: nitro, cyano, C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or                C₁-C₄-alkylthio, as mentioned above in particular;            -   a 5-membered heteroaromatic moiety which is linked via a                nitrogen atom, contains one to three nitrogen atoms and                can carry one or two halogen atoms and/or one or two of                the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,                C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or                C₁-C₄-alkylthio. Particular mention may be made of:                1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl,                3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl,                4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl,                4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl,                1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl,                5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl,                3,4-dichloro-1-imidazolyl;            -   R¹⁰ is furthermore a group

-   -   -   -    where R¹¹ and R¹², which can be identical or different,                are:                -   C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,                    C₃-C₈-cycloalkyl, it being possible for these                    radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio                    and/or an unsubstituted or substituted phenyl                    radical, as mentioned above in particular;                -   phenyl which can be substituted by one or more, eg.                    e.g., one to three, of the following radicals:                    halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,                    C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio,                    where these radicals are, in particular, those                    mentioned above;                -   or R¹¹ and R¹² together form a C₃-C₁₂-alkylene chain                    which can carry one to three C₁-C₄-alkyl groups and                    contain a heteroatom from the group consisting of                    oxygen, sulfur and nitrogen, as mentioned in                    particular for R⁷ and R⁸.;

    -   g) R¹ is furthermore a radical

-   -    where R¹³ is:        -   C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl            as mentioned above in particular, it being possible for            these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio            and/or a phenyl radical as mentioned above; or        -   phenyl, unsubstituted or substituted, in particular as            mentioned above.;    -   h) R¹ is a radical

-   -    where R¹³ has the abovementioned meaning.        -   R can furthermore be:            -   tetrazole [sic] or nitrile [sic].

In respect of the biological effect, preferred carboxylic acidderivatives of the general formula I, both as pure enantiomers and purediastereomers or as mixture thereof, are those where the substituentshave the following meanings:

-   -   R² is hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, the C₁-C₄-alkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio        groups and halogen atoms mentioned in detail for R¹, especially        chlorine, methyl, methoxy, ethoxy, difluoromethoxy,        trifluoromethoxy;    -   X is nitrogen or CR¹⁴ where    -   R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4-        to 5-membered alkylene or alkenylene ring in which, in each        case, a methylene group can be replaced by oxygen or sulfur,        such as —CH₂—CH₂—O—, —CH═CH—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—CH₂O—,        in particular hydrogen, —CH₂—CH₂—O—, —CH(CH₃)—CH(CH₃)—O—,        —C(CH₃)═C(CH₃)—O—, —CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S—;    -   R³ the is hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, C₁-C₄-alkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio        groups and halogen atoms mentioned for R¹, especially chlorine,        methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or R³        is linked to R¹⁴ as mentioned above to give a 5- or 6-membered        ring;    -   R⁴ and R⁵ are phenyl or naphthyl, which can be substituted by        one or more, eg. e.g., one to three, of the following radicals:        halogen, nitro, cyano, hydroxyl, mercapto, amino, C₁-C₄-alkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₁-C₄-alkylthio, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino,        C₁-C₄-alkylcarbonyl, C₁C₄-alkoxycarbonyl; phenyl or naphthyl,        which are connected together in the ortho positions by a direct        linkage, a methylene, ethylene or ethenylene group, an oxygen or        sulfur atom or an —SO₂—, —NH— or, N-alkyl group, or        C₃-C₇-cycloalkyl;    -   R⁶ is C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or        C₃-C₈-cycloalkyl as mentioned above in particular, it being        possible for these radicals in each case to be substituted one        or more times by: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy,        C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio,        C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, hydroxycarbonyl,        C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino or        unsubstituted or substituted phenyl or phenoxy, as mentioned        above in particular;        -   phenyl or naphthyl, which can be substituted by one or more            of the following radicals: halogen, nitro, cyano, hydroxyl,            amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,            C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, C₁-C₄-akylamino            [sic] alkylamino or C₁-C₄-dialkylamino, as mentioned in            particular for R⁷ and R⁴; or        -   a five- or six-membered heteroaromatic moiety which contains            one to three nitrogen atoms and/or one sulfur or oxygen atom            and which can carry one to four halogen atoms and/or one or            two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl,            phenoxy or phenylcarbonyl, it being possible for the phenyl            radicals in turn to carry one to five halogen atoms and/or            one to three of the following radicals: C₁-C₄-alkyl,            C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or            C₁-C₄-alkylthio, as mentioned for R⁴ in particular;    -   Y is sulfur, oxygen or a single bond;    -   Z is sulfur, oxygen, —SO—, —SO₂—or a single bond.

Particularly preferred compounds of the formula I, both as pureenantiomers and pure diastereomers or as mixture thereof, are those inwhich the substituents have the following meanings:

-   -   R² is C₁-C₄-alkyl, or C₁-C₄-alkoxy;    -   X is nitrogen or CR¹⁴, where    -   R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4-        or 5-membered alkylene or alkenylene ring such as —CH₂—CH₂—CH₂—,        —CH═CH—CH₂—, in which in each case a methylene group can be        replaced by oxygen or sulfur, such as —CH₂—CH₂—O—, —CH═CH—O—,        —CH₂—CH₂—CH₂—O—, —CH═CH—CH₂O—, in particular hydrogen,        —CH₂—CH₂—O—, —CH(CH₃)—CH(CH₃)—O—, —C(CH₃)═C(CH₃)—O—,        —CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S—;    -   R³ the is C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio groups        mentioned for R¹, or R³ is linked to R¹⁴ as mentioned above to        give a 5- or 6-membered ring;    -   R⁴ and R⁵ are phenyl (identical or different) which can be        substituted by one or more, eg. e.g., one to three, of the        following radicals: halogen, nitro, hydroxyl, C₁-C₄-alkyl,        C₁-C₄-alkoxy, C₁-C₄-alkylthio; or    -   R⁴ and R⁵ are phenyl groups which are connected together in the        ortho positions by a direct linkage, a methylene, ethylene or        ethenylene group, an oxygen or sulfur atom or an SO₂, NH or        N-alkyl group; or    -   R⁴ and R⁵ are C₃-C₇-cycloalkyl;    -   R⁶ is C₁-C₈-alkyl, C₃-C₆-alkenyl or C₃-C₈-cycloalkyl, it being        possible for these radicals in each case to be substituted one        or more times by: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy,        C₃-C₆-alkenyloxy, C₁-C₄-alkylthio; or        -   R⁶ is phenyl or naphthyl, which can be substituted by one or            more of the following radicals: halogen, nitro, cyano,            hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,            C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, C₁-C₄-akylamino            [sic] or C₁-C₄-dialkylamino; or        -   R⁶ is a five- or six-membered heteroaromatic moiety which            contains a nitrogen atom and/or a sulfur or oxygen atom and            which can carry one to four halogen atoms and/or one or two            of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy, C₁-C₄-alkylthio, phenyl, phenoxy or            phenylcarbonyl, it being possible for the phenyl radicals in            turn to carry one to five halogen atoms and/or one to three            of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy and/or C₁-C₄-alkylthio;    -   Y is sulfur, oxygen or a single bond;    -   Z is sulfur, oxygen, —SO—, —SO₂— or a single bond.

The compounds of the present invention provide a novel therapeuticpotential for the treatment of hypertension, pulmonary hypertension,myocardial infarct, angina pectoris, acute kidney failure, renalinsufficiency, cerebral vasospasms, cerebral ischemia, subarachnoidhemorrhages, migraine, asthma, atherosclerosis, endotoxic shock,endotoxin-induced organ failure, intravascular coagulation, restenosisafter angioplasty, benign prostate hyperplasia, or hypertension orkidney failure caused by ischemia or intoxication.

The good effect of the compounds can be shown in the following tests:

Receptor binding studies

Cloned human ET_(A) receptor-expressing CHO cells and guinea pigcerebellar membranes with >60% ET_(B) compared with ET_(A) receptorswere used for binding studies.

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ mediumcontaining 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA).

After 48 h, the cells were washed with PBS and incubated with 0.05%trypsin-containing PBS for 5 min. Neutralization was then carried outwith F₁₂ medium, and the cells were collected by centrifugation at300×g. To lyze lyse the cells, the pellet was briefly washed with lysisbuffer (5 mM Tris-IICl, pII 7.4 with 10% glycerol) and then incubated ata concentration of 107 cells/ml of lysis buffer at 4° C. for 30 min. Themembranes were centrifuged at 20,000×g for 10 min, and the pellet wasstored in liquid nitrogen.

Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizerand [lacuna] obtained by differential centrifugation at 1000×g for 10min and repeated centrifugation of the supernatant at 20,000×g for 10min.

Binding assays

For the ET_(A) and ET_(B) receptor binding assay, the membranes weresuspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl₂,40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of proteinper assay mixture and incubated with 25 pM [125I] [¹²⁵I]-ET₁ (ET_(A)receptor assay) or 25 pM [125I] [¹²⁵I]-RZ₃ (ET_(B) receptor assay) inthe presence and absence of test substance at 25° C. The nonspecificbinding was determined using 10⁻⁻⁷ 10⁻⁷ M ET₁. After 30 min, the freeand bound radioligand were separated by filtration through GF/B glassfiber filters (Whatman, England) on a Skatron cell collector (Skatron,Lier, Norway) and the filters were washed with ice-cold Tris-HCl buffer,pH 7.4 with 0.2% BSA. The radioactivity collected on the filters wasquantified using a Packard 2200 CA liquid scintillation counter.

Functional in vitro assay system to look for endothelin receptor(subtype A) antagonists

This assay system is a functional, cell-based assay for endothelinreceptors. When certain cells are stimulated with endothelin 1 (ET1)they show an increase in the intracellular calcium concentration. Thisincrease can be measured in intact cells loaded with calcium-sensitivedyes.

1-Fibroblasts which had been isolated from rats and in which anendogenous endothelin receptor of the A subtype had been detected wereloaded with the fluorescent dye Fura 2-an Fura 2-am as follows: aftertrypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5mM KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH 7.4) toa density of 2×10⁶/ml and incubated with Fura 2-am (2 μM), PluronicsF-127 (0.04%) und and DMSO (0.2%) at 37° C. in the dark for 30 min. Thecells were then washed twice with buffer A and resuspended at 2×10⁶/ml.

The fluorescence signal from 2×10⁵ cells per ml with Ex/Em 380/510 wasrecorded continuously at 30° C. The test substances and, after anincubation time of 3 min, ET1 [lacuna] to the cells, the maximum changein the fluorescence was determined. The response of the cells to ET1without previous addition of a test substance was used as control andwas set equal to 100%.

Testing of ET antagonists in vivo

Male SD rats weighting 250-300 g were anesthetized with amobarbital,artifically artificially ventilated, vagotomized and pithed. The carotidartery and jugular vein were cathetized [sic] catheterized.

In control animals, intravenous administration of 1 μg/kg ET1 led to adistinct rise in blood pressure which persisted for a lengthy period.

The test animals received an i.v. injection of the test compounds (1ml/kg) 5 min before the administration of ET1. To determine theET-antagonistic properties, the rise in blood pressure in the testanimals was compared with that in the control animals.

Endothelin-1-induced sudden death in mice

The principle of the test is the inhibition of the sudden heart deathcaused in mice by endothelin, which is probably induced by constrictionof the coronary vessels, by pretreatment with endothelin receptorantagonists. Intravenous injection of 10 nmol/kg endothelin in a volumeof 5 ml/kg of body weight results in death of the animals within a fewminutes.

The lethal endothelin-1 dose is checked in each case on a small group ofanimals. If the test substance is administered intravenously, theendothelin-1 injection which was lethal in the reference group usuallytakes place 5 min thereafter. With other modes of administration, thetimes before administration are extended, where appropriate up toseveral hours.

The survival rate is recorded, and effective doses which protect 50% ofthe animals (ED 50) from endothelin-induced heart death for 24 h orlonger are determined.

Functional test on vessels for endothelin receptor antagonists

Segments of rabbit aorta are, after an initial tension of 2 g and arelaxation time of 1 h in Krebs-Henseleit solution at 37° C. and pH7.3-7.4, first induced to contract with K⁺. After washing out, anendothelin dose-effect plot up to the maximum is constructed.

Potential endothelin antagonists are administered to other preparationsof the same vessel 15 min before starting the endothelin dose-effectplot. The effects of the endothelin are calibrated as a % of theK⁺-induced contraction. Effective endothelin antagonists result in ashift to the right in the endothelin dose-effect plot.

The compounds according to the invention can be administered orally orparenterally (subcutaneously, intravenously, intramuscularly,intraperotoneally intraperitoneally) in a conventional way.Administration can also take place with vapors or sprays through thenasopharyngeal space.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. The daily dose of active substance is, asa rule, about 0.5-50 mg/kg of body weight on oral administration andabout 0.1-10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, eg. e.g., as uncoated or (film-) coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. The activesubstances can for this purpose be processed with conventionalpharmaceutical aids such as tablet binders, fillers, preservatives,tablet disintegrants, flow regulators, plasticizers, wetting agents,dispersants, emulsifiers, solvents, release-slowing agents, antioxidantsand/or propellent gases (cf. H. Sucker et al.: PharmazeutischeTechnologie, Thieme-Verlag, Stuttgart, 1991). The administration formsobtained in this way normally contain from 0.1 to 90% by weight of theactive substance.

Synthesis examples Example 1

Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate weredissolved in 50 ml of absolute methanol and, at 0° C., 0.1 ml of borontrifluoride etherate was added. The mixture was stirred at 0° C. for 2 hand at room temperature for a further 12 h. The solvent was distilledout, the residue was taken up in ethyl acetate, washed with sodiumbicarbonate solution and water and dried over magnesium sulfate. Afterremoval of the solvent by distillation there remained 5.5 g (88%) of apale yellow oil.

Example 2

Methyl 2-hydroxy-3-phenoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60mmol) of phenol were heated together at 100° C. for 6 h. Removal of theexcess phenol by distillation under high vacuum and purification of theresidue by chromatography on silica gel with hexane/ethyl acetatemixtures resulted in 4.9 g (77%) of a pale yellow oil.

Example 3

Methyl2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate

2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) ofsodium hydride was added. The mixture was stirred for 1 h and then 2.2 g(10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. Afterstirring at room temperature for 24 h, cautious hydrolysis was carriedout with 10 ml of water, the pH was adjusted to 5 with acetic acid, andthe solvent was removed by distillation under high vacuum. The residuewas taken up in 100 ml of ethyl acetate, washed with water and driedover magnesium sulfate, and the solvent was distilled out. The residuewas mixed with 10 ml of ether, and the resulting precipitate wasfiltered off with suction. After drying, 3.48 g (82%) of a white powderremained.

Melting point 81° C.

Example 4

2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

2.12 g (5 mmol) of methyl2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml of dioxane, 10 ml of 1N KOH solution were added,and the mixture was stirred at 100° C. for 3 h. The solution was dilutedwith 300 ml of water and extracted with ethyl acetate to removeunreacted ester. The aqueous phase was then adjusted to pH 1-2 withdilute hydrochloric acid and extracted with ethyl acetate. After dryingover magnesium sulfate and removal of the solvent by distillation, theresidue was mixed with an ether/hexane mixture, and the precipitatewhich formed was filtered off with suction. After drying, 1.85 g (90%)of a white powder remained.

Melting point 167° C.

Example 5

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl sodium [sic]propionate

1.68 g (4 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic acidare dissolved in 4 ml of 1N NaOH+100 ml of water. The solution isfreeze-dried, and the sodium salt of the carboxylic acid used isobtained quantitatively.

10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml each of methanol and glacial acetic acid, 1 mlof RuO(OH)₂ in dioxane was added, and hydrogenation was carried out withH₂ in an autoclave at 100° C. under 100 bar for 30 h. The catalyst wasfiltered off, the mixture was concentrated, mixed with ether and washedwith NaCl solution, and the organic phase was dried and concentrated.10.1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate wereobtained as an oil.

Example 7

Methyl2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methoxy-3,3-diphenylpropionate[sic]

7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml of dichloromethane, 3 g (30 mmol) oftriethylamine were added, and 3.2 g (28 mmol) of methanesulfonylchloride were added dropwise while stirring. The mixture was stirred atroom temperature for 2 h, washed with water, dried over magnesiumsulfate and concentrated under reduced pressure. The residue was takenup in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodiumbicarbonate in 100 ml of DMF. After stirring at room temperature for 2 hand at 60° C. for a further 2 h, the mixture was poured into 1 liter ofice-water, and the resulting precipitate was filtered off with suction.After drying, 3.19 g (29%) of a white powder remained.

Example 8

Methyl 2-hydroxy-3,3-diphenylbutyrate

1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in10 ml of absolute ether were added dropwise to a cup-rate solution whichhad been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normalmethyllithium solution and had been cooled to −78° C. The solution wasstirred at −78° C. for 1 h and then allowed to warm to room temperature.It was subsequently diluted with 100 ml of ether and 100 ml of water,and the ether phase was washed with dilute citric acid and with sodiumbicarbonate solution and dried over magnesium sulfate. The crude productwas purified by chromatography on silica gel with cyclohexane/ethylacetate mixtures to result in 250 mg (16%) of a pale yellow oil.

Example 9

2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodiummethoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) atroom temperature. After cooling to −100° C., 92.24 g (0.85 mol) ofmethyl chloroacetate were added in such a way that the internaltemperature rose to 40° C. while continuing to cool in a bath at −10° C.The mixture was then stirred without cooling at the autogenoustemperature for one hour. After addition of 250 ml of water and briefstirring, the aqueous phase was separated off. The MTB phase was washedwith 250 ml of dilute sodium chloride solution. After the solvent hadbeen changed to methanol (250 ml), a solution of 1 g ofp-toluenesulfonic acid in 10 ml of methanol was added at roomtemperature. The mixture was stirred at autogenous temperature for onehour and then heated to reflux. While distilling out the methanol, 400 gof a 10% strength sodium hydroxide solution was added dropwise, andfinally 60 ml of water were added. The methanol was distilled out untilthe bottom temperature reached 97° C. After cooling to 55° C., 190 ml ofMTB were added and the mixture was acidified to pH 2 with about 77 ml ofconcentrated HCl. After cooling to room temperature, the aqueous phasewas separated off and the organic phase was concentrated by distillingout 60 ml of MtB [sic] MTB. The product was crystallized by adding 500ml of heptane and slowly cooling to room temperature. The coarselycrystalline solid was filtered off with suction, washed with heptane anddried to constant weight in a vacuum oven at 40° C.

Yield: 108.9 g (80%), HPLC >99.5% area.

Example 10

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolutionwith L-proline methyl ester)

148.8 g of a 30% strength methanolic sodium methanolate solution (0.826mol) were added dropwise to 240 g of a 57% strength methanolic L-prolinemethyl ester hydrochloride solution (0.826 mol) at room temperature, and2.41 of MTB and 225 g (0.826 mol) of2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After 2680 mlof MTB/methanol mixture had been distilled out with simultaneousdropwise addition of 2.4 l of MTB, the mixture was slowly cooled to roomtemperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionicacid x L-proline methyl (ester) were filtered off with suction, and thesolid was washed with 150 ml of MTB. The filtrate was concentrated bydistilling out 1.5 l of MTB, and 1.0 l of water was added. The pH wasadjusted to 1.2 with concentrated hydrochloric acid at room temperatureand, after stirring and phase separation, the aqueous phase wasseparated off and extracted with 0.4 l of MTB. The combined organicphases were extracted with 0.4 l of water. The residue after the MTB hadbeen stripped off was dissolved in 650 ml of toluene under reflux, andthe product was crystallized by seeding and slow cooling. Filtrationwith suction, washing with toluene and drying in a vacuum oven resultedin 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35%based on the racemate).

Chiral HPLC: 100% pure; HPLC: 99.8%

Example 11

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolutionwith (S)-1-(4-nitrophenyl)ethylamine)

30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750ml of acetone and 750 ml of MTB under reflux, the mixture was seeded,boiled under reflux for one hour and slowly cooled to room temperaturefor crystallization. The crystals(S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x(S)-1-(4-nitrophenyl) ethylamine) were filtered off with suction andwashed with MTB. The residue was suspended in 500 ml of water and 350 mlof MTB and then the pH was adjusted to 1.2 with concentratedhydrochloric acid at room temperature, and, after stirring and phaseseparation, the aqueous phase was separated off and extracted with 150ml of MTB. The combined organic phases were extracted with 100 ml ofwater. 370 ml of MTB were distilled out and then 390 ml of n-heptanewere added under reflux, and the mixture was slowly cooled to roomtemperature while the product crystallized. Filtration with suction,washing with n-heptane and drying in a vacuum oven resulted in 35.0 g ofS-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on theracemate).

Chiral HPLC: 100% pure; HPLC: 99.8%

Example 12

Benzyl3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate

24.48 g (90 mmol) of 3-methoxy-3,3-diphenyl-2-hydroxypropionic acid weredissolved in 150 ml of DMF, and 13.7 g (99 mmol) of potassium carbonatewere added. The suspension was stirred at room temperature for 30 min.Then 10.7 ml (90 mmol) of benzyl bromide were added dropwise over thecourse of 5 min, and the mixture was stirred for 1 h, during which thetemperature rose to 32° C.

To this mixture were successively added 24.84 g (180 mmol) of K₂CO₃ and20.52 g (90 mmol) of2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentapyridine [sic], andthe mixture was stirred at 80° C. for 3 h.

For workup, the contents of the flask were diluted with about 600 ml ofH₂O and cautiously acidified with concentrated HCl, and 250 ml of ethylacetate were added. 31.4 g of pure product precipitated and werefiltered off.

The ethyl acetate phase was separated from the mother liquor, theaqueous phase was extracted again with ethyl acetate, and the combinedorganic phases were concentrated. The oily residue (19 g) was purifiedby chromatography (cyclohexane/ethyl acetate=9/1) to result in a further10.5 g of pure product.

Total yield: 41.9 g (82.2 mmol)=91%; Melting point 143-147° C.; MS:MH⁺=511

Example 13

3-Methoxy-2-(4-methoxy-(6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3,3-diphenylpropionic[sic] acid

40 g (78.4 mmol) of benzyl3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionatewere dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mgof palladium on active carbon (10%) were added, and the mixture wasexposed to a hydrogen atmosphere until no further gas was taken up. Thecatalyst was filtered off, the solution was evaporated, and the residuewas crystallized from ether.

Example 14

Ethyl 2S-3,3-diphenyloxirane-2-carboxylate

2.57 g (10.2 mnol) of ethyl 3,3-diphenylacrylate and 464 mg of4-phenylpyridine N-oxide were dissolved in 24 ml of methylene chloride,and 432 mg (6.5 mol %) of(5,5)-(+)-N,N′-bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III)chloride were added. While cooling in ice, 6.4 ml of a 12% strengthsodium hypochloride [sic] solution were added, and the mixture wasstirred while cooling in ice for 30 min and at room temperatureovernight. The solution was diluted to 200 ml with water, extracted withether, dried and evaporated. 2.85 g of a colorless oil were obtained.Purification by NPLC [sic] HPLC (cyclohexane:ethyl acetate=9:1) resultedin 1.12 g of oil with an enantiomer ratio of about 8:1 in favor of the Sconfiguration.

¹H-NMR [CDCl₃], δ=1.0 (t, 3H); 3.9 (m, 3H); 7.3 (m, 10H)

Example 15

2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol [sic]

46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g (192mmol) of 5-methylisothiourea [sic] sulfate were successively added to29.6 g (528 mmol) of KOH in 396 ml of methanol, and the mixture wasstirred at room temperature overnight, acidified with 1N hydrochloricacid and diluted with water. The crystals which separated out werefiltered off with suction and dried. 20 g of crystals were obtained.

Example 16

sulfanylSulfanyl4-Chlorochloro-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine [sic]

255 ml of phosphorus oxychloride were added to 20 g (110 mmol) [lacuna],and the mixture was stirred at 80° C. for 3 hours. Phosphorusoxychloride was evaporated off, ice was added to the residue, and thecrystals which separated out were filtered off with suction. 18.5 g of abrownish solid were obtained.

Example 17

4-Methoxy-2-methylsulfonyl-6,7-dihydro-5II-cyclopentapyrimidine [sic]

18.05 g (90 mmol) of4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine [sic] weredissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide(as 30% strength solutions [sic] in methanol) were added dropwise, andthe mixture was stirred for 2 hours. The solution was evaporated, takenup in ethyl acetate and acidified with dilute hydrochloric acid, and theethyl acetate extract was evaporated. 15.5 g of an oil remained.

¹H-NMR [DMSO], δ=2.1 (quintet, 2H); 2.5 (s, 3H); 2.8 (dt, 4H); 3.9 (s,3H) ppm

Example 18

2-Methylsulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentopyrimidine [sic]

15 g (76.2 mmol) of4-methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine [sic]were dissolved in 160 ml of glacial acetic acid/methylene chloride(1:1), and 1.3 g of sodium tungstate were added. At 35° C., 17.5 ml (170ml [sic]) of a 30% strength H₂O₂ solution were added dropwise. Themixture was then diluted with 500 ml of water and 100 ml of methylenechloride, and the organic phase was separated off, dried and evaporated.14 g of oil remained and were crystallized from ether.

¹H-NMR [CDCl₃], δ=2.2 (quintet, 2H); 3.0 (dt., 4H); 3.3 (s, 3H); 4.1 (s,3H) ppm

Example 19

1-Benzenesulfonyl-3-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxy-4,4-diphenyl-2-butanone

0.37 g (2.4 mmol) of phenyl methane [sic] sulfone were dissolved in 10ml of dry THF and then, at −70° C., 2 eq. of butyllithium (2.94 ml; 1.6molar solution in hexane) were added dropwise. After 1 h at −70° C., 1 g(2.4 mmol) of methyl2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropynoate[sic] dissolved in 5 ml of THF was added dropwise. The reaction mixturewas then stirred at −70° C. for 1 h and at −10° C. for 1 h and thenwarmed to room temperature. For workup, about 10 ml of saturated NH₄Clsolution were added dropwise, thorough extraction with ethyl acetate wascarried out, and the combined organic phases [lacuna] with-saturatedN-Cl [sic] solution and dried over Na₂SO₄. The residue obtained afterdrying and concentration was purified by chromatography on silica gel(n-heptane/ethyl acetate 15%→30%) and subsequently MPLC HPLC on RPsilica gel (acetonitrile/H₂O+TFA); 0.3 g of a white amorphous powder wasobtained as product.

Example 20

3,3-Diphenyloxiram-2-carbonitrile [sic]

3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of dry THFand then, at −10° C., a mixture of 5 g (27.4 mmol) of benzophenone and4.2 g (54.9 mmol) of chloroacetonitrile was added dropwise.

The reaction mixture was stirred at −10° C. for about 2 h, then pouredinto water and extracted several times with ethyl acetate. The combinedorganic phases were dried over Na₂SO₄ and concentrated, and the residuewas purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 1.2 g (20%)

¹H-NMR [CDCl₃], δ=3.9 (s, 1H); 7.4-7.5 (m, 10 H) ppm

Example 21

2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile

6.5 [lacuna] g (29.4 mmol) of 3,3-diphenyloxirane-2-carbonitrile weredissolved in 60 ml of methanol and, at 0° C., about 2 ml of borontriffuoride etherate solution were added. The mixture was stirredfurther at 0° C. for 1 h and then at room temperature overnight. Forworkup it was diluted with diethyl ether and washed with saturated NaClsolution, and the organic phase was dried over Na₂SO₄ and concentrated.The residue comprised 7.3 g of a white amorphous powder which was useddirectly in the subsequent reactions.

¹H-NMR [CDC₁₃][CDCl₃], δ=2.95 (broad s, OH), 3.15 (s, 3H), 5.3 (s, 1H),7.3-7.5 (m, 10) ppm

Example 22

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionitrile

7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile weredissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K₂CO₃ and 6.3 g (28mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. Themixture was stirred at room temperature for about 12 h, then poured intowater and extracted with ethyl acetate. The combined organic phases werewashed again with H₂O, dried and concentrated. The residue obtained inthis way was then purified by chromatography on silica gel(n-hepane/ethyl acetate).

Yield: 6.9 g of white amorphous powder

FAB-MS: 392 (M+H⁺) ¹H-NMR [CDCl₃], δ=3.3 (s, 3H); 4.95 (s, 6H), 5.85 (s,1H); 6.3 (s, 1H); 7.3-7.5 (m, 10H) ppm

Example 23

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-tetrazole[sic]

0.5 g (1.3 mmol) of nitrile was dissolved in 10 ml of toluene, and 85 mg(1.3 mmol) of NaN₃ and 460 mg (1.4 mmol) of Bu₃SnCl were successivelyadded, and then the mixture was refluxed for about 40 h. Cooling wasfollowed by dilution with ethyl acetate and washing with 10% aqueous KFsolution and with NaCl solution. After drying over MgSO₄ andconcentration there remained 1.0 g of a yellow oil, which was purifiedby chromatography on silica gel (n-heptane/ethyl acetate).

Concentration of the fractions resulted in 60 mg of the 1H-tetrazole and110 mg of the 1-methyltetrazole, each as amorphous white solids.

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-tetrazole[sic]

Electrospray-MS: 435 (M+H⁺) ¹H-NMR (CDCl₃): δ (ppm) 3.28 (s, 3H), 3.85(s, 6H), 5.75 (s, 1H), 7.25-7.40 (m, 10H), 7.50 (s, 1H).

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1-methyltetrazole[sic]

Electrospray-MS; 471 (M+H⁺) ¹H-NMR (CDCl₃): δ (ppm) 3.0 (s, 3H), 3.35(s, 3H9) [sic], 3.80 (s, 6H), 5.75 (s, 1H), 7.30-7.40 (m, 11H).

Example 24

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfinyl-3,3-diphenylpropionicacid

1.2 g (2.9 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic[sic] acid were introduced into 15 ml of glacial acetic acid at 0° C.and 294 μl of 30% strength H₂O₂ were added dropwise. The mixture wasstirred at room temperature overnight, poured into water, extracted withCH₂Cl₂ and washed with sodium thiosulfate solution and brine. Afterdrying, 1 g of substance was isolated as a white foam.

Example 25

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionicacid

0.6 g (1.45 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methyl-sulfonyl-3,3-diphenylpropionic[sic] acid was introduced into 15 ml of glacial acetic acid at roomtemperature, and 294 μl of 30% strength H₂O₂ were added dropwise. Themixture was stirred at room temperature overnight, heated at 50° C. fora further 3 h, poured into water and washed with sodium thiosulfatesolution and brine. After drying, 400 mg were isolated as a white solid.

The compounds listed in Table 1 [sic] can be prepared in a similar way.

TABLE 1

m.p. No. R¹ R⁴, R⁵ R⁶ R² R³ X Y Z [° C.] I-195I-1 OMeOCH₃ Phenyl MethylOMeOCH₃ OMeOCH₃ CH O O 81 I-196I-2 OH Phenyl Methyl OMeOCH₃ OMeOCH₃ CH OO 167 I-197I-3 OH Phenyl CH₂—CH₂—S—CH₃ OMeOCH₃ OMeOCH₃ CH O O I-198I-4OH Phenyl Ethyl OMeOCH₃ OMeOCH₃ CH O O 81 (decomp.) I-199I-5 OH Phenyliso-Propyl OMeOCH₃ OMeOCH₃ CH O O 182 I-200I-6 OH Phenyl Methyl OMeOCH₃OMeOCH₃ CH O S 168 I-201I-7 OH Phenyl CH₂—CH₂—SO₂— OMeOCH₃ OMeOCH₃ CH OO CH(CH₃)₂ I-202I-8 OH Phenyl CH₂—CH₂—SO₂— OMeOCH₃ OMeOCH₃ CH S OCH(CH₃)₂ I-203I-9 OH Phenyl CH₂—CH₂—SO₂— OMeOCH₃ OMeOCH₃ C—CH(CH₃)₂ O OCH(CH₃)₂ I-204I-10 OH Phenyl CH₂—CH₂—SO₂— OMeOCH₃ OMeOCH₃ C—CH(CH₃)₂ O OCH(CH₃)₂ I-205I-11 OH Phenyl CH₂—CH₂—SO₂— OMeOCH₃ NH•OCH₃ CH O OCH(CH₃)₂ I-206I-12 OH Phenyl n-Propyl OMeOCH₃ OMeOCH₃ CH O O 174I-207I-13 OMeOCH₃ Phenyl n-Propyl OMeOCH₃ OMeOCH₃ CH O O I-208I-14 OHPhenyl n-Propyl OEtOC₂H₅ OEtOC₂H₅ CH O O I-209I-15 OH Phenyl n-ButylOMeOCH₃ OMeOCH₃ CH O O I-210I-16 OH Phenyl iso-Butyl OMeOCH₃ OMeOCH₃ CHO O I-211I-17 OH Phenyl iso-Butyl OMeOCH₃ O—CH₂—CH₂—C O O I-212I-18 OHPhenyl tert.-Butyl OMeOCH₃ OMeOCH₃ CH O O I-213I-19 OH PhenylCyclopropyl OMeOCH₃ OMeOCH₃ CH O O I-214I-20 OH Phenyl CyclopentylOMeOCH₃ OMeOCH₃ CH O O I-215I-21 OH Phenyl Cyclohexyl OMeOCH₃ OMeOCH₃ CHO O I-216I-22 OH Phenyl (CH₃)₃C—CH₂—CH₂ OEtOC₂H₅ OEtOC₂H₅ CH O OI-217I-23 OH Phenyl (CH₃)₂CH—CH₂— OMeOCH₃ OMeOCH₃ CH O O 173 CH₂—CH₂I-218I-24 OH Phenyl HO—CH₂—CH₂ OMeOCH₃ OMeOCH₃ CH O O I-219I-25 OHPhenyl HO₂C—CH₂)₂— OMeOCH₃ OMeOCH₃ CH O O I-220I-26 OH PhenylCyclopropyl- OMeOCH₃ OMeOCH₃ CH O O 115 methylene [sic] I-221I-27 OHPhenyl H OMeOCH₃ OMeOCH₃ CH O O I-222I-28 OH Phenyl Methyl OMeOCH₃OMeOCH₃ CH O — I-223I-29 OH Phenyl Phenyl OMeOCH₃ OMeOCH₃ CH O O 136I-224I-30 OH Phenyl Phenyl OMeOCH₃ O—CH(CH₃)—CH₂—C O O I-225I-31 OHPhenyl Phenyl OMeOCH₃ OMeOCH₃ CH O O I-226I-32 OH Phenyl4-Isopropyl-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-227I-33 OH Phenyl4-Methyl-S-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-228I-34 OH Phenyl4-Methyl-O-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-229I-35 OH Phenyl3-Ethyl-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-230I-36 OH Phenyl2-Methyl-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-231I-37 OH Phenyl 2-Cl-PhenylOMeOCH₃ OMeOCH₃ CH O O I-232I-38 OH Phenyl 3-Br-Phenyl OMeOCH₃ OMeOCH₃CH O O I-233I-39 OH Phenyl 4-F-Phenyl OMeOCH₃ OMeOCH₃ CH O O I-234I-40OH Phenyl 4-F-Phenyl OMeOCH₃ OMeOCH₃ CH S O I-235I-41 OH Phenyl4-CH₃—Phenyl OMeOCH₃ OMeOCH₃ CH O O I-236I-42 OH Phenyl 3-NO₂—PhenylOMeOCH₃ OMeOCH₃ CH O O I-237I-43 OH Phenyl 2-HO—Phenyl OMeOCH₃ OMeOCH₃CH O O I-238I-44 OH Phenyl 3,4- OMeOCH₃ OMeOCH₃ CH O O DimethoxyphenylI-239I-45 OH Phenyl 3,4- OMeOCH₃ OMeOCH₃ CH O O Dioxomethylene-phenyl-[sic] I-240I-46 OH Phenyl 3,4,5- OMeOCH₃ OMeOCH₃ CH O OTriimethoxyphenyl I-241I-47 OH Phenyl Benzyl OMeOCH₃ OMeOCH₃ CH O OI-242I-48 OH Phenyl 2-Cl—Benzyl OMeOCH₃ OMeOCH₃ CH O O I-243I-49 OHPhenyl 3-Br—Benzyl OMeOCH₃ OMeOCH₃ CH O O I-244I-50 OH Phenyl 4-F—BenzylOMeOCH₃ OMeOCH₃ CH O O I-245I-51 OH Phenyl 2-Methyl-Benzyl OMeOCH₃OMeOCH₃ CH O O I-246I-52 OH Phenyl 2-Methyl-Benzyl OMeOCH₃ O—CH═CH—C O OI-247I-53 OH Phenyl 3-Ethyl-Benzyl OMeOCH₃ OMeOCH₃ CH O O I-248I-54 OHPhenyl 4-iso-Propyl-Benzyl OMeOCH₃ OMeOCH₃ CH O O I-249I-55 OH Phenyl4-NO₂—Propyl- OMeOCH₃ OMeOCH₃ CH O O Benzyl I-250I-56 OH Phenyl2-Methyl-5-Propyl- OMeOCH₃ OMeOCH₃ CH O O Benzyl I-251I-57 OH Phenyl2-Methyl-5-Propyl- OEtOC₂H₅ OEtOC₂H₅ CH O O Benzyl I-252I-58 OH Phenyl4-Methyl-2-Propyl- OMeOCH₃ OMeOCH₃ CH O O Benzyl I-253I-59 OH Phenyl3,4-Dioxomethyl- OMeOCH₃ OMeOCH₃ CH O O enebenzyl [sic] I-254I-60 OH4-F—Phenyl 4-Methyl-2-Propyl- OMeOCH₃ OMeOCH₃ CH O O 163-165 Benzyl(decomp.) I-255I-61 OMeOCH₃ 4-F—Phenyl Methyl OEtOC₂H₅ OEtOC₂H₅ CH O OI-256I-62 OH 4-Cl—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O I-257I-63 OH4-Methyl—O—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O I-258I-64 OH4-Methyl—O—Phenyl Ethyl OMeOCH₃ OMeOCH₃ CH O O I-259I-65 OH4-Methyl-Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O I-260I-66 OH4-Methyl-Phenyl Methyl OMeOCH₃ O—CH₂—CH₂—C O O I-261I-67 OH 3-CF₃—Phenyln-Propyl OMeOCH₃ OMeOCH₃ CH O O I-262I-68 OH 3-CF₃—Phenyl n-PropylOMeOCH₃ O—CH(CH₃)—CH₂—C O O I-263I-69 OH 4-NO₂—Phenyl Methyl OMeOCH₃OMeOCH₃ CH O O I-264I-70 OH 4-NO₂—Phenyl Methyl OMeOCH₃ O—CH═CH—C O OI-265I-71 OH 3-Cl—Phenyl Ethyl OMeOCH₃ OMeOCH₃ CH O O I-266I-72 OH2-F—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O 193-194 (decomp.) I-267I-73 OH2-F—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH S O I-268I-74 OH 2-Methyl—O—PhenylMethyl OMeOCH₃ OMeOCH₃ CH O O I-269I-75 OH 2-Methyl—O—Phenyl MethylOMeOCH₃ OMeOCH₃ CH O S I-270I-76 OH 3,4-Dimethoxyphenyl Methyl OMeOCH₃OMeOCH₃ CH O O I-271I-77 OH 3,4-Dioxmethyl- Methyl OMeOCH₃ OMeOCH₃ CH OO enephenyl [sic] I-272I-78 OH p-CF₃—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH OO I-273I-79 OH Phenyl Methyl OMeOCH₃ OEtOC₂H₅ CH O O I-274I-80 OMeOCH₃Phenyl Methyl OMeOCH₃ OEtOC₂H₅ CH O O I-275I-81 OH Phenyl Ethyl OMeOCH₃NH—OMe CH O O OCH₃ I-276I-82 OH p-Methyl-O—Phenyl n-Propyl OMeOCH₃ OCF₃CH O O I-277I-83 OH Phenyl Methyl OMeOCH₃ CF₃ CH O O I-278I-84 OH PhenylMethyl OMeOCH₃ CF₃ N O O I-279I-85 OH 3,4-Dimethoxyphenyl Benzyl MethylMethyl O O I-280I-86 OH 3,4-Dimethoxyphenyl Methyl OMeOCH₃ O—CH₂CH₂—C OO I-281I-87 OH Phenyl Methyl OMeOCH₃ O—CH₂—CH₂—C O O 126 (decomp.)I-282I-88 OH Phenyl Methyl OMeOCH₃ O—CH(CH₃)—CH₂—C O O I-283I-89 OHPhenyl Methyl OMeOCH₃ N(CH₃)—CH═CH—C O O 118 I-284I-90 OH Phenyl MethylOMeOCH₃ S—C(CH₃)═C(CH₃)—C O O I-285I-91 OH Phenyl Methyl OMeOCH₃O—C(CH₃)═CH—C O O I-286I-92 OH Phenyl Methyl Methyl O—C(CH₃)═CH—C O OI-287I-93 OH Phenyl Methyl Methyl O—CH═CH—C O O I-288I-94 OH 4-F—PhenylMethyl Methyl S—CH═CH—C O O I-289I-95 OH 4-F—Phenyl H OMeOCH₃ OMeOCH₃ CHO S I-290I-96 OH Phenyl Methyl OMeOCH₃ CH₂—CH₂—CH₂—C O O 149-151(decomp.) I-291I-97 OH Phenyl Methyl Methyl CH₂—CH₂—CH₂—C O O 157(decomp.) I-292I-98 OH Phenyl Methyl Ethyl CH₂—CH₂—CH₂—CH₂—C O OI-293I-99 OH Phenyl Methyl OMeOCH₃ CH₂—CH₂—CH₂—CH₂—C O O I-294I-100 OHPhenyl Methyl Methyl Methyl CH O O I-295I-101 OH Phenyl Methyl EthylEthyl CH O O I-296I-102 OH Phenyl Methyl Methyl Methyl C—CH₃ O OI-297I-103 OH Phenyl Methyl OMeOCH₃ MeCH₃ CH O O I-298I-104 OHCyclohexyl Methyl OMeOCH₃ OMeOCH₃ CH O O I-299I-105 OH Cyclohexyl MethylOMeOCH₃ CH₂—CH₂—CH₂—C O O I-300I-106 OH Phenyl Methyl OCH₃ OCH₃ CH S SI-301I-107 OH Phenyl Methyl OCH₃ OCH₃ CH O S 134 I-302I-108 OCH₃ PhenylMethyl OCH₃ OCH₃ CH S S I-303I-109 OH Phenyl Methyl OCH₃ OCH₃ CH O OI-304I-110 OCH₃ 2-Fluorophenyl Methyl OCH₃ OCH₃ CH O O I-305I-111 OC₂H₅3-Chlorophenyl Methyl OCH₃ OCH₃ N O O I-306I-112 ON(CH₃)₂ 4-BromophenylMethyl CF₃ CF₃ CH S O I-307I-113 O—CH₂— Phenyl Ethyl OCH₃ CF₃ CH O OC═CH I-308I-114 OH Phenyl Propyl OCH₃ OCF₃ CH O S I-309I-115 OCH₃ Phenyli-Propyl OCH₃ CH₃ CH O O I-310I-116 OC₂H₅ Phenyl s-Butyl OCH₃ Cl CH S OI-311I-117 ON(CH₃)₂ 2-Methylphenyl Methyl OCH₃ OCH₃ CH O O I-312I-118ON(CH₃)₂ 3-Methoxyphenyl Methyl OCH₃ OCH₃ CH O O I-313I-119 ON═C(CH₃)₂4-Nitrophenyl Methyl OCH₃ OCH₃ CH O O I-314I-120 ON(CH₃)₂ Phenyl1-Phenylpropyn-3-yl OCH₃ OCF₃ N O S I-315I-121 ON═C(CH₃)₂2-Hydroxyphenyl Methyl OCH₃ CH₃ N O O I-316I-122 ONSO₂(C₆H₅3-Trifluoromethyl- Methyl OCH₃ Cl N O O phenyl I-317I-123 NHPhenyl—4-Dimethyl- Methyl OCH₃ OCH₃ CH S O phenyl aminophenyl I-318I-124 OC₂H₅Phenyl Trifluoromethyl CH₃ CH₃ CH O O I-319I-125 ON(CH₃)₂ Phenyl BenzylCl Cl CH O O I-320I-126 ON(CH₃)₂ Phenyl 2-Methoxyethyl OCH₃ —O—CH₂—CH₂—S O I-321I-127 OH Phenyl Phenyl OCH₃ OCH₃ CH O O I-322I-128 OH PhenylPhenyl OCH₃ —O—CH₂—CH₂— O O I-323I-129 OH Phenyl Phenyl OCH₃ OCH₃ N O OI-324I-130 OH Phenyl Phenyl OCH₃ OCH₃ CH S O I-325I-131 OH Phenyl PhenylOCH₃ OCH₃ CH S S I-326I-132 OH Phenyl Phenyl OCH₃ OCH₃ CH O S I-327I-133OH Phenyl Phenyl OCH₃ OCH₃ CH O O I-328I-134 OH Phenyl Phenyl OCH₃ OCH₃CH O O I-329I-135 OH —(CH₂)₅— Phenyl Phenyl OCH₃ CH O O I-330I-136 OHPhenyl 2-thiozolyl2- OCH₃ OCH₃ CH O O thiazolyl I-331I-137 OCH₃2-Fluorophenyl Phenyl OCH₃ OCH₃ CH O O I-332I-138 OC₂H₅ 3-ChlorophenylPhenyl OCH₃ OCH₃ N O O I-333I-139 ON(CH₃)₂ 4-Bromophenyl Phenyl CF₃ CF₃CH O O I-334I-140 OCH2CH Phenyl 2-Fluorophenyl OCH₃ CF₃ CH O O OCH2═CHI-335I-141 OH Phenyl 3-Chlorophenyl OCH₃ OCF₃ CH O S I-336I-142 OCH₃Phenyl 4-Bromophenyl OCH₃ CH₃ CH O O I-337I-143 OC₂H₅ Phenyl 4-ThiazolylOCH₃ Cl CH S O I-338I-144 ON(CH₃)₂ 2-Methylphenyl Phenyl OCH₃ OCH₃ CH OO I-339I-145 ON═C(CH₃)₂ 2-Methoxyphenyl Phenyl OCH₃ OCH₃ CH O OI-340I-146 OH Phenyl Methyl OCH₃ —CH₂—CH₂—CH₂—C O O I-341I-147 OH4-Fluorophenyl Methyl OCH₃ OCH₃ CH O O 168 (decomp.) I-342I-148 OH4-Fluorophenyl Methyl OCH₃ —CH₂—CH₂—CH₂—C O O I-343I-149 NH—SO—C₆H₅4-Nitrophenyl Phenyl OCH₃ OCH₃ CH O O I-344I-150 OCH₃ Phenyl3-Imidazolyl OCH₃ —O—CH₂—CH₂ O O I-345I-151 OC₂H₅ Phenyl 4-ImidazolylOCH₃ CF₃ N S O I-346I-152 ON(CH₃)₂ Phenyl 2-Pyrazolyl OCH₃ OCF₃ N O SI-347I-153 ON═C(CH₃)₂ 2-Hydroxyphenyl Phenyl OCH₃ CH₃ N O O I-348I-154NH—SO₂—C₆H₅ 3-Trifluoromethyl- Phenyl OCH₃ Cl N O O phenyl I-349I-155NHPhenyl— 4-Dimethylamino- Phenyl OCH₃ OCH₃ CH S O phenyl phenylI-350I-156 ONa Phenyl Phenyl OCH₃ OCH₃ CH S S I-351I-157 O—CH₂—C≡CPhenyl Phenyl OCH₃ OCH₃ N S S I-352I-158 OH Phenyl Phenyl CF₃ CF₃ CH O SI-353I-159 OCH₃ Phenyl Phenyl OCF₃ OCF₃ CH O O I-354I-160 OC₂H₅ Phenyl2-Dimethylamino- CH₃ CH₃ CH O O phenyl I-355I-161 ONC(CH₃)₂ Phenyl3-Hydroxyphenyl Cl Cl CH O O I-356I-162 ON═C(CH₃)₂ Phenyl4-Trifluoromethyl- OCH₃ —O—CH₂—CH₂— S O phenyl I-357I-163 NH—SO₂—C₆H₅Phenyl 2-Oxazolyl OCH₃ CF₃ N S S I-358I-164 OH Phenyl Methyl CH₃ CH₃ CHO O I-359I-165 OH Cyclohexyl Methyl OCH₃ OCH₃ CH O O I-360I-166 OHCyclohexyl Methyl OCH₃ CH₂—CH₂—CH—C O O I-361I-167 OH Phenyl MethylN(CH₃)₂ N(CH₃)₂ CH O O I-362I-168 OH Phenyl Methyl OCH₃ OCH₃ CH O SO₂I-363I-169 OH Phenyl Methyl OCH₃ OCH₃ CH O SO₂ I-364I-170 OH 3-F—PhenylMethyl OMeOCH₃ OMeOCH₃ CH O O I-365I-171 OH 3-F—Phenyl Methyl OMeOCH₃CH₂—CH₂—CH₂—C O O I-366I-172 OH 4-F—Phenyl Methyl OMeOCH₃ CH₂—CH₂CH₂—C OO 142-143 191° C. I-367I-173 OH 3-Methyl—O—Phenyl Methyl OMeOCH₃CH₂—CH₂—CH₂—C O O 158-161 (decomp.) I-368I-174 OH 3-Methyl—O—PhenylMethyl OMeOCH₃ OMeOCH₃ CH O O I-369I-175 OH 3-Methyl—O—Phenyl EthylOMeOCH₃ CH₂—CH₂—CH₂—C O O I-370I-176 OH Phenyl HO—CH₂—CH₂ OMeOCH₃CH₂—CH₂—CH₂—C O O I-371I-177 OH Phenyl Methyl NMe₂ NMe₂ N O O 181N(CH₃)₂ N(CH₃)₂ I-372I-178 OH Phenyl Methyl OMeOCH₃ OMeOCH₃ N O OI-323I-179 OH 3-F—Phenyl Methyl OCH₃ CH₃ CH O O I-374I-180 NH—SO₂—Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O Phenyl I-375I-181 NH—SO₂—Me PhenylMethyl OMeOCH₃ OMeOCH₃ CH O O CH₃ I-376I-182 CH₂—SO₂— Phenyl MethylOMeOCH₃ OMeOCH₃ CH O O Phenyl I-377I-183 NH—SO₂—Me Phenyl Methyl OMeOCH₃OMeOCH₃ CH O O CH₃ I-378I-184 —CN Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O OI-379I-185 Tetrazole[sic] Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O OI-380I-186 NH—SO₂— Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O 167 PhenylI-381I-187 N—Methyltetra- Phenyl Methyl OMeOCH₃ OMeOCH₃ CH O O zole[sic]I-382I-188 ONa Phenyl Methyl OMeOCH₃ —O—CH₂—CH₂—C— O O 122-139 (decomp.)(zers.) I-383I-189 OH o-F—Phenyl Methyl OMeOCH₃ —O—CH₂—CH₂—C— O O140-144 (decomp.) I-384I-190 OH m-Methyl-Phenyl Methyl OMeOCH₃ OMeOCH₃CH O O 169-177 I-385I-191 OH m-Methyl-Phenyl Methyl OMeOCH₃—O—CH₂—CH₂—C— O O 119-135 (decomp.) I-386I-192 OH p-F—Phenyl MethylOMeOCH₃ MeCH₃ CH O O 137-140 (decomp.) I-387I-193 OH m-F—Phenyl MethylMethyl —O—CH₂—CH₂—C— O O 150-152 I-388I-194 OH p-F—Phenyl Methyl Methyl—O—CH₂—CH₂—C— O O 169-170

TABLE II

m.p. No. R¹ A R⁶ R² R³ X Y Z [° C.] II-1 OH Bond Methyl OMethyl OMethylCH O O 96-98 II-2 OH CH₂ Methyl OMethyl OMethyl CH O O II-3 OH CH₂—CH₂Methyl OMethyl OMethyl CH O O II-4 OH CH═CH Methyl OMethyl OMethyl CH OO II-5 OH O Methyl OMethyl OMethyl CH O O II-6 OH S Methyl OMethylOMethyl CH O O II-7 OH NH(CH₃) Methyl OMethyl OMethyl CH O O II-8 OHBond Isopropyl OMethyl OMethyl CH O O 137-139 II-9 OH Bondp-Isopropylphenyl OMethyl OMethyl CH O O II-10 OH Bond Benzyl OMethylOMethyl CH O O II-11 OH CH═CH Ethyl OMethyl OMethyl CH O O II-12 OHCH═CH (CH₃)₂—CH₂—CH₂ OMethyl OMethyl CH O O II-13 OH CH═CHCyclopropylmethyl OMethyl OMethyl CH O O ene[sic] II-14 OH CH═CH MethylOMethyl O—CH₂—CH₂—C O O II-15 OH CH₂—CH₂ Ethyl OMethyl O—CH═CH—C O OII-16 OH CH₂═CH₂ Methyl OMethyl CH₂—CH₂—CH₂—C O O CH₂—CH₂ II-17 OH BondMethyl OMethyl CH₂—CH₂—CH₂—C O O 147

Example 35

Receptor binding data were measured by the binding assay described abovefor the compounds listed below. The results are shown in Table 2 [sic].

TABLE 2 Receptor binding data (K_(i) values) Compound ET_(A) [nM] ET_(B)[nM] I-2 6 34 I-29 86 180 I-5 12 160 I-4 7 2500 I-87 1 57 I.89 86 9300I-103 0.4 29 I-107 3 485 I-12 19 1700 I-26 23 2000 I-23 209 1100 I-47150 1500 I-60 33 970 I-96 0.6 56 II-3 107 7300 II-1 28 2300

We claim:
 1. A compound of the formula I

where R is formyl, tetrazole, nitrile, a COOH group —CO₂H or a radicalwhich can be hydrolyzed to COOH, and the other substituents have thefollowing meanings: —CO₂H; R² is hydrogen, hydroxyl, —NH₂,—NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, orC₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; X isCR¹⁴, where R¹⁴ is hydrogen or C₁-C₅-alkyl; R³ is hydrogen, hydroxyl,—NH₂, —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, halogen, C₁-C₄-alkyl, orC₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, NH—O—C₁-C₄-alkyl,C₁-C₄-alkylthio or CR³ is linked to CR¹⁴ as indicated above to give a 5-or 6-membered ring; R⁴ and R⁵, which can be identical or different, arephenyl or naphthyl, which can be substituted by one or more of thefollowing radicals selected from the group consisting of: halogen,nitro, cyano, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino orand C₁-C₄-dialkylamino; or R⁴ and R⁵ are phenyl or naphthyl, which areconnected together in the ortho position via a direct linkage, amethylene, ethylene or ethenylene group, an oxygen or sulfur atom or, anSO₂, NH or N-alkyl group; or a C₃-C₇-cycloalkyl group; R⁶ is hydrogen,or R⁶ is C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or C₃-C₈-cycloalkyl,where each of these radicals can be substituted by one or more times bysubstituents selected from the group consisting of: halogen, nitro,cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy,C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₃-C₈-alkylcarbonylalkyl, C₁-C₄-alkylamino,di-C₁-C₄-alkylamino, phenyl or and phenoxy which phenyl or phenoxy issubstituted by one or more times by substituents selected from the groupconsisting of: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or and C₁-C₄-alkylthio; or phenyl ornaphthyl, each of which can be substituted by one or more of thefollowing radicals selected from the group consisting of: halogen,nitro, cyano, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio,C₁-C₄-alkylamino, C₁-C₄-dialkylamino , dioxomethylene or anddioxoethylene; or a five or six-membered heteroaromatic moietycontaining (i) one to three nitrogen atoms, and/or one sulfur or oxygenatom (ii) one sulfur atom, (iii) one oxygen atom, (iv) one to threenitrogen atoms and one sulfur atom, or (v) one to three nitrogen atomsand one oxygen atom, which heteroaromatic moiety can carry one or moresubstituents selected from the group consisting of: one to four halogenatoms and/or, and one or two of the following radicals selected from thegroup consisting of: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl, phenoxy or andphenylcarbonyl, it being possible for the phenyl radicals in turn tocarry one or more substituents selected from the group consisting of:one to five halogen atoms and/or, and one to three of the followingradicals selected from the group consisting of: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;,Y is sulfur or, oxygen or a single bond; and Z is sulfur, oxygen, —SO—or —SO₂—.
 2. The compound of the formula I as defined in claim 1,wherein X is CR¹⁴ and R¹⁴ is hydrogen.
 3. The compound of the formula Ias defined in claim 2, wherein R is CO₂H.
 4. The compound of the formulaI as defined in claim 2, wherein R² and R³ each is methoxy.
 5. Thecompound of the formula I as defined in claim 2, wherein R⁴ and R⁵ eachis phenyl.
 6. The compound of the formula I as defined in claim 2,wherein R⁶ is C₁-C₈-alkyl.
 7. The compound of the formula I as definedin claim 2, wherein Y is oxygen.
 8. The compound of the formula I asdefined in claim 2, wherein Z is oxygen or sulfur.
 9. The compound ofthe formula I as defined in claim 8, wherein Z is oxygen.
 10. Thecompound of the formula I as defined in claim 1, wherein X is CH, Y isoxygen, Z is oxygen, R is CO₂H, R² is methoxy, R³ is methoxy, R⁴ isphenyl, R⁵ is phenyl, R⁶ is methyl, ethyl or iso-propyl.
 11. Thecompound of the formula I as defined in claim 1, wherein R is tetrazole,nitrile or a group

where R¹ has the following meanings: a) hydrogen; b) succinylimidoxy; c)a five-membered heteroaromatic ring linked by a nitrogen atom, selectedfrom the group consisting of: pyrrolyl, pyrazolyl, imidazolyl andtriazolyl, which ring can carry one or more substituents selected fromthe group consisting of: one or two halogen atoms and or, and one or twoof the following radicals selected from the group consisting of:C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or andC₁-C₄-alkylthio; d) a radical

 where m is 0 or 1 and R⁷ and R⁸, which can be identical or different,have the following meanings: hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl,C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, where these alkyl, cycloalkyl, alkenyland alkynyl groups can each carry one or more substituents selected fromthe group consisting of: one to five halogen atoms and/or, and one ortwo of the following groups selected from the group consisting of:C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₃-C₆-alkenyloxy, C₃-C₆-alkenylthio, C₃-C₆-alkynyloxy orC₃-C₆-alkynylthio, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl,C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl, C₃-C₆-alkenyloxycarbonylor and C₃-C₆-alkynyloxycarbonyl,; phenyl, which can be substituted byone or more times by substituents selected from the group consisting of:halogen, nitro, cyano, C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or,C₁-C₄-alkylthio, and di-C₁-C₄-alkylamino, or R⁷ and R⁸ together form aC₄-C₇-alkylene chain which can be substituted by C₁-C₄-alkyl, and maycontain a hetero atom selected from the group consisting of: oxygen,sulfur and nitrogen, or R⁷ and R⁸ together form a CH₂—CH═CH—CH₂ orCH═CH—(CH₂)₃ chain; e) a radical

 where k is 0, 1 and 2, p is 1, 2, 3 and 4, and R⁹ is C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or phenyl, which can besubstituted by one or more times by substituents selected from the groupconsisting of: halogen, nitro, cyano, C₃-C₆-alkenylcarbonyl,C₃-C₆-alkynylcarbonyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or and C₁-C₄-alkylthio; f) a radical OR¹⁰, where R¹⁰ ishydrogen, the cation of an alkali metal or an alkaline earth metal or anenvironmentally compatible organic ammonium ion; C₃-C₈-cycloalkyl whichmay carry one to three C₁-C₄-alkyl groups; C₁-C₈-alkyl which may carryone or more substituents selected from the group consisting of: one tofive halogen atoms and/or, and one of the following radicals selectedfrom the group consisting of: C₁-C₄-alkoxy, C₁-C₄-alkylthio, cyano,C₁-C₄-alkylcarbonyl, C₃-C₈-cycloalkyl, C₁-C₄-alkoxycarbonyl, phenyl,phenoxy or and phenylcarbonyl, where the aromatic radicals substituentsin turn may carry one or more substituents selected from the groupconsisting of: one to five halogen atoms and/or, and one to three of thefollowing radicals selected from the group consisting of: nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/orC₁-C₄-alkylthio; C₁-C₈-alkyl which may carry one to five halogen atomsand which carries one of the following radicals selected from the groupconsisting of: a 5-membered heteroaromatic ring containing one to threenitrogen atoms or, a nitrogen atom and an oxygen or and a nitrogen atomand a sulfur atom, which may carry one or more substituents selectedfrom the group consisting of: one to four halogen atoms and/or, and oneor two of the following radicals selected from the group consisting of:nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio; C₂-C₆-alkyl which carries oneof the following radicals in position 2: C₁-C₄-alkoxyimino,C₃-C₆-alkynyloxyimino, C₃-C₆-haloalkenyloxyimino or benzyloxyimino;C₃-C₆-alkenyl or C₃-C₆-alkynyl which may carry one to five halogenatoms; phenyl which may carry one or more substituents selected from thegroup consisting of: one to five halogen atoms and/or, and one to threeof the following radicals selected from the group consisting of: nitro,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxyand/or C₁-C₄-alkylthio; a 5-membered heteroaromatic ring which is bondedvia a nitrogen atom and containing one to three nitrogen atoms, whichmay carry one or more substituents selected from the group consistingof: one or two halogen atoms, and or one or two of the followingradicals selected from the group consisting of: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/orC₁-C₄-alkylthio; a radical

 where R¹ R¹¹ and R¹², which may be identical or different are:C₁-C8-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it beingpossible for these radicals to carry a one or more substituents selectedfrom the group consisting of: C₁-C₄-alkoxy, C₁-C₄-alkylthio, and/orphenyl, which may carry one or more substituents selected from the groupconsisting of: one to five halogen atoms and/or, and one to three of thefollowing radicals selected from the group consisting of: nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/orC₁-C₄alkylthio; phenyl which may carry one or more of the followingradicals selected from the group consisting of: halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or andC₁-C₄-alkylthio; or R¹¹ and R¹² together form a C₃-C₁₂-alkylene chainwhich may carry one to three C₁-C₄-alkyl groups and which may contain ahetero atom selected from the group consisting of: a nitrogen, oxygenand sulfur; g) a radical

 where R¹³ is C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,C₃-C₈-cycloalkyl, it being possible for these radicals to carry one ormore substituents selected from the group consisting of: a C₁-C₄-alkoxy,a C₁-C₄-alkylthio and/or a phenyl radical, and a phenyl; or phenyl whichmay carry one or more of the following radicals selected from the groupconsisting of: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or and C₁-C₄-alkylthio.
 12. The compoundof the formula I as defined in claim 1, wherein R is —CO₂H or a radicalwhich can be hydrolyzed to —CO₂H; R⁴ is phenyl; and R⁵ is phenyl. 13.The compound of the formula I as defined in claim 12, wherein X is CH; Yis oxygen; Z is oxygen; R is —CO₂H; R² is C₁-C₄-alkyl; R³ isC₁-C₄-alkyl; and R⁶ is C₁-C₈-alkyl.
 14. The compound of the formula I asdefined in claim 13, wherein R² is methyl; and R³ is methyl.
 15. Thecompound of the formula as defined in claim 1, wherein R is formyl,—CO₂H or a radical which can be hydrolyzed to —CO₂H; R² is C₁-C₄-alkyl;X is CR¹⁴, where R¹⁴ is hydrogen or C₁-C₅-alkyl; R³ is C₁-C₄-alkyl; R⁴and R⁵ which can be identical or different, are phenyl, which can besubstituted by one or more of the following selected from the groupconsisting of: halogen, nitro, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy andC₁-C₄-alkylthio; or phenyl which are connected together in the orthopositions by a direct linkage, methylene, ethylene, ethenylene, oxygen,sulfur, —SO₂—, —NH— or N-alkyl group; or C₃-C₇-cycloalkyl; R⁶ isC₁-C₈-alkyl, C₃-C₆-alkenyl or C₃-C₈-cycloalkyl, where each of these canbe substituted by one or more substituents selected from the groupconsisting of: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy,C₃-C₆-alkenyloxy and C₁-C₄-alkylthio; or phenyl or naphthyl, each ofwhich can be substituted by one or more of the following selected fromthe group consisting of: halogen, nitro, cyano, hydroxyl, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, C₁-C₄-alkylamino and C₁-C₄-dialkylamino; or a five- orsix-membered heteroaromatic moiety containing (i) a nitrogen atom, (ii)a sulfur atom, (iii) an oxygen atom, (iv) a nitrogen atom and a sulfuratom, or (v) a nitrogen atom and an oxygen atom, which heteroaromaticmoiety can carry one or more substituents selected from the groupconsisting of: one to four halogen atoms, and one or two of thefollowing selected from the group consisting of: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, phenyl, phenoxy andphenylcarbonyl, it being possible for the phenyl in turn to carry one ormore substituents selected from the group consisting of: one to fivehalogen atoms, and one to three of the following selected from the groupconsisting of: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-alkylthio; Y is sulfur, oxygen or a single bond; and Z is sulfur,oxygen, SO or SO₂.
 16. The compound of the formula I as defined in claim15, wherein R is —CO₂H; R² is C₁-C₄-alkyl; X is CR¹⁴, where R¹⁴ ishydrogen; R³ is C₁-C₄-alkyl; R⁴ and R⁵ which can be identical ordifferent, are phenyl, which can be substituted by one or more of thefollowing selected from the group consisting of: halogen, nitro,hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylthio; R⁶ isC₁-C₈-alkyl, which can by substituted by one or more substituentsselected from the group consisting of: halogen, hydroxyl, nitro, cyano,C₁-C₄-alkoxy, C₃-C₆-alkenyloxy and C₁-C₄-alkylthio; Y is oxygen; and Zis oxygen.
 17. The compound of the formula I as defined in claim 16,where R⁴ and R⁵ are each phenyl.
 18. The compound of the formula I asdefined in claim 1, wherein R is —CO₂H or a radical which can behydrolyzed to —CO₂H; R² is C₁-C₄-alkyl; X is CR¹⁴, where R¹⁴ ishydrogen; R³ is C₁-C₄-alkyl; R⁴ and R⁵ which can be identical ordifferent, are phenyl, which can be substituted by one or more of thefollowing selected from the group consisting of: halogen, nitro,hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylthio; R⁶ isC₁-C₈-alkyl, which can be substituted by one or more substitutentsselected from the group consisting of: halogen, hydroxyl, nitro, cyano,C₁-C₄-alkoxy, C₃-C₆-alkenyloxy and C₁-C₄-alkylthio; Y is oxygen; and Zis oxygen.
 19. The compound of the formula I as defined in claim 18,where R⁴ and R⁵ are each phenyl.
 20. The compound of the formula I asdefined in claim 1, wherein R is —CO₂H; R² is C₁-C₄-alkyl; X is CR¹⁴,where R¹⁴ is hydrogen or C₁-C₅-alkyl; R³ is C₁-C₄-alkyl; R⁴ and R⁵ arephenyl which can be substituted by one or more halogen atoms; R⁶ isC₁-C₈-alkyl or C₃-C₈-cycloalkyl, where each of these can be substitutedone or more times by phenyl, or phenyl; Y is oxygen; and Z is sulfor oroxygen.
 21. The compound of the formula I as defined in claim 1, whereinR is —CO₂H or a radical which can be hydrolyzed to CO₂H; R² is halogen,C₁-C₄-alkyl or C₁-C₄-haloalkyl; X is CR¹⁴, where R¹⁴ is hydrogen orC₁-C₅-alkyl; R³ is halogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl; R⁴ and R⁵are phenyl, which can be substituted by one or more of the followingselected from the group consisting of: halogen, nitro, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylamino and C₁-C₄-dialkylamino;R⁶ is hydrogen, or R⁶ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, where each ofthese can be substituted by one or more substituents selected from thegroup consisting of: halogen, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkylthioand phenyl which is substituted by one or more substituents selectedfrom the group consisting of: halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-alkylthio; or phenyl which can be substituted byone or more of the following selected from the group consisting of:halogen, nitro, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio anddioxomethylene; or a five or six-membered heteroaromatic moietycontaining (i) one to three nitrogen atoms, (ii) one sulfur atom, (iii)one oxygen atom, (iv) one to three nitrogen atoms and one sulfur atom,or (v) one to three nitrogen atoms and one oxygen atom whichheteroaromatic moiety can carry one to four halogen atoms; Y is sulfuror oxygen; and Z is sulfur or oxygen.
 22. The compound of claim 21,wherein R is —CO₂H, —COOCH₃, —COON(CH₃)₂, —COOCH₂C≡CH, —COOC₂H₅,—COON═C(CH₃)₂, —COONH-phenyl, —COOCH═CH₂ or —CONH—SO—C₆H₅; R² is —Cl,—CH₃, —CH₂CH₃ or —CF₃; X is CR¹⁴, where R¹⁴ is hydrogen; R³ is —Cl,—CH₃, —CH₂CH₃ or —CF₃; R⁴ and R⁵ are phenyl, which can be substituted byone or more groups selected from the group consisting of: —F, —Cl, —Br,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, —NO₂ and —N(CH₃)₂; R⁶ is —H, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —C(CH₃)₃, —CH₂CH(CH₃)₂, cyclopropyl, —CH₂CH₂CH₂CH(CH₃)₂,—CH₂—CH₂—S—CH₃, —CH₂CH₂OH, phenyl, trifluoroethyl, p-isopropyl-phenyl,p-methyl-S-phenyl, p-methyl-O-phenyl, m-ethyl-phenyl, o-methyl-phenyl,o-Cl-phenyl, m-Br-phenyl, p-F-phenyl, p-methyl-phenyl, m-NO₂-phenyl,o-HO-phenyl, 3,4-dimethoxy-phenyl, 3,4-dioxomethylene-phenyl,3,4,5-trimethoxy-phenyl, benzyl, o-Cl-benzyl, m-Br-benzyl, p-F-benzyl,o-methyl-benzyl, m-ethyl-benzyl or p-isopropyl-benzyl; Y is sulfur oroxygen; and Z is sulfur or oxygen.
 23. The compound of claim 22, whereinR⁴ and R⁵ are each phenyl.
 24. A compound of the formula I:

where R is —CO₂H; R² is C₁-C₄-alkyl; X is CR¹⁴, where R¹⁴ is hydrogen;R³ is C₁-C₄-alkyl; R⁴ and R⁵ which can be identical or different, arephenyl, which can be substituted by one or more of the followingselected from the group consisting of: halogen, nitro, hydroxyl,C₁-C₄-alkyl, C₁-C₄-alkoxy and C₁-C₄-alkylthio; R⁶ is a C₁-C₈-alkyl,which can be substituted by one or more substituents selected from thegroup consisting of: halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy,C₃-C₆-alkenyloxy and C₁-C₄-alkylthio; Y is oxygen; and Z is oxygen. 25.The compound of the formula I as defined in claim 24, wherein R⁴ and R⁵are each phenyl.